This invention is directed to the tetradecapeptides ##STR2## in which Y is L-Cha, L-Leu, or D-Phe as well as to their pharmaceutically acceptable acid addition salts and to intermediates produced during the synthesis of the tetradecapeptides.
Somatostatin (also known as somatotropin release inhibiting factor) is a tetradecapeptide of the formula ##STR3## This tetradecapeptide was isolated from ovine hypothalamic extracts and was found to be active in inhibiting the secretion of growth hormone (GH), also known as somatotropin. In this regard, see P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science, 179, 77 (1973).
The biologically active tetradecapeptides of this invention have the formula defined above and include the non-toxic acid addition salts thereof. Their structures differ from that of somatostatin by the presence of a D-phenylalanine residue, an L-cyclohexylalanine residue, or an L-leucine residue in position 11 in place of an L-phenylalanine residue. For convenience sake, the tetradecapeptides of this invention can be referred to as D-Phe.sup.11 -somatostatin; L-Cha.sup.11 -somatostatin; and L-Leu.sup.11 -somatostatin.
Thus, this invention is directed to a compound selected from those of the formula ##STR4## and their pharmaceutically-acceptable non-toxic acid addition salts, and R-L-Ala-Gly-L-Cys(R.sub.1)-L-Lys(R.sub.2)-L-Asn-L-Phe-L-Phe-L-Trp(R.sub.5) -L-Lys(R.sub.2)-L-Thr(R.sub.3)-Y-L-Thr(R.sub.3)-L-Ser(R.sub.4)-L-Cys(R.sub. 1)-X; in which p1 Y is D-PHe, L-Cha, or L-Leu;
R is hydrogen or an .alpha.-amino protecting group; PA1 R.sub.1 is hydrogen or a thio protecting group; PA1 R.sub.2 is hydrogen or an .epsilon.-amino protecting group; PA1 R.sub.3 and R.sub.4 each are hydrogen or a hydroxy protecting group; PA1 R.sub.5 is hydrogen or formyl; and PA1 X is hydroxy or ##STR5## IN WHICH THE RESIN IS POLYSTYRENE; WITH THE PROVISO THAT, WHEN X is hydroxy, each of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is hydrogen, and, when X is ##STR6## each of R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is other than hydrogen. PA1 H-l-ala-Gly-L-Cys-L-Lys-L-Asn-L-Phe-L-Phe-L-Trp-L-Lys-L-Thr-D-Phe-L-Thr-L-S er-L-Cys-OH; PA1 H-l-ala-Gly-L-Cys-L-Lys-L-Asn-L-Phe-L-Phe-L-Trp-L-Lys-L-Thr-L-Cha-L-Thr-L-S er-L-Cys-OH; PA1 H-l-ala-Gly-L-Cys-L-Lys-L-Asn-L-Phe-L-Phe-L-Trp-L-Lys-L-Thr-L-Leu-L-Thr-L-S er-L-Cys-OH; ##STR7## PA1 Ala - Alanine PA1 Asn - Asparagine PA1 Cha - Cyclohexylalanine PA1 Cys - Cysteine PA1 Gly - Glycine PA1 Lys - Lysine PA1 Phe - Phenylalanine PA1 Ser - Serine PA1 Thr - Threonine PA1 Trp - Tryptophan PA1 Dcc - n,n'-dicyclohexylcarbodiimide PA1 Dmf - n,n-dimethylformamide PA1 Boc - t-Butyloxycarbonyl PA1 Pmb - p-Methoxybenzyl PA1 CbzOC - o-Chlorobenzyloxycarbonyl PA1 Cpoc - cyclopentyloxycarbonyl PA1 Bzl - Benzyl PA1 For - Formyl PA1 BpOC - 2-(p-biphenylyl)isopropyloxycarbonyl